The role of cell autonomous complement in B cell function and regulation

Abstract

B cells are a cornerstone of the adaptive immune response as they not only differentiate into antibody-producing plasma cells, mediating protection from pathogens, but also have several antibody-independent, immune-regulatory functions. Even with these essential roles, some aspects of their function and regulation are not fully understood, including the role of complement system - an ancient arm of the innate immune system that also plays a key role in B cell biology. It is well-known that extracellular complement receptor signaling, and complement-tagging of antigen is necessary for the activation and amplification of the B cell response. However, it is unclear if intracellular, cell-autonomous complement signaling occurs, and/or plays an important role, in the function of B cells in a similar manner to that described in T cells. In this thesis, I explore if an intracellular complement system exists in B cells and investigate its role in immune responses, with a focus on C5. We show that both mouse and human B cells express C5, C5aR1, and C5aR2, and that modulation of these complement proteins leads to altered B cell responses in vitro. We further demonstrate that cell-autonomous complement plays an important role in B cells responses in vivo, as mice lacking the ability to produce cell-autonomous complement from B cells have altered germinal center and antigen-specific antibody responses following immunization. Single-cell RNA sequencing of immunized mice implicated B cell C5 in the regulation of proliferative and metabolic pathways. Additionally, we found that cell-autonomous C5 has differing effects in male and female B cells. Taken together, our data suggest that cell-autonomous complement may play a previously unappreciated and crucial role in modulating B cells responses in different contexts, and that this function may be subject to sexual dimorphism.